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The authors review the opioid literature for evidence of increased analgesia and reduced adverse side effects by combining mu-opioid-receptor (MOR) agonists, kappa-opioid-receptor (KOR) agonists, and nonselective low-dose-opioid antagonists (LD-Ant). We tested fentanyl (MOR agonist) and spiradoline (KOR agonist), singly and combined, against somatic and visceral pain models. Combined agonists induced additive analgesia in somatic pain and synergistic analgesia in visceral pain. Other investigators report similar effects and reduced tolerance and dependence with combined MOR agonist and KOR agonist. LD-Ant added to either a MOR agonist or KOR agonist markedly enhanced analgesia of either agonist. In accordance with other place-conditioning (PC) studies, our PC investigations showed fentanyl-induced place preference (CPP) and spiradoline-induced place aversion (CPA). We reduced fentanyl CPP with a low dose of spiradoline and reduced spiradoline CPA with a low dose of fentanyl. We propose combined MOR agonist, KOR agonist, and LD-Ant to produce superior analgesia with reduced adverse side effects, particularly for visceral pain.

Interactions of opioid agonists, fentanyl and oxymorphone (micro-selective) and spiradoline and enadoline(kappa-selective), were examined for additive, sub-additive, or supra-additive antinociception in the colorectal distension (CRD) assay. Single-dose values (mg/kg, 0.006-0.016 for fentanyl, 0.25-1.26 forspiradoline, etc.) were summed to formulate theoretical additive-dose plots for comparison with actual combined-dose effects. Combined fentanyl and spiradoline yielded additive (low-dose levels) or supraadditive(high-dose levels) effects. Single and combined doses of fentanyl (0.012 mg/kg) and spiradoline(0.3 mg/kg) were tested after pretreatment with saline, beta-funaltrexamine (b-FNA, micro-selective antagonist), or nor-binaltorphimine (n-BNI, kappa-selective antagonist). Supra-additive effects of combined agonists were attenuated by either antagonist (greater with n-BNI). But paradoxical patterns of antagonism of single-dose effects occurred: the fentanyl antinociception was not antagonized by b-FNA, whereas the spiradoline antinociception was. The results indicate complex interactions of agonists in this visceral pain model and potential for combined agonists to improve pain relief with decreased side effects

Spiradoline (U62066E) a racemic mixture of the two enantiomers U63639(+) and U63640(-), appears to have kappa opioid receptor activity, but the contribution of each enantiomer toward this activity is still in question. To determine the activity of each enantiomer in comparison to the racemic mixture, the three forms were tested in the cold-water tail-flick (CWTF) assay in male Sprague-Dawley rats. Antinociception by spiradoline was completely antagonized by naloxone 0.50 mg/kg, a dose five times that required to antagonize antinociception by fentanyl in this same assay. In a second series of tests, fentanyl-induced antinociception was markedly reduced, while spiradoline-induced antinociception was essentially unchanged. in methadone-tolerant animals. Of the enantiomers, only U63640 produced antinociception, whereas U63639 failed to affect the nociceptive response. Additionally, spiradoline failed to produce antinociception in animals pretreated with norbinaltorphimine (kappa receptor specific), but antinociception was not affected in animals pretreated with beta-funaltrexamine (mu receptor specific). These results show that spiradoline is a full antinociceptive agonist in the CWTF assay and that the effects of the drug are mediated through kappa opioid receptors.

Changes in colonic motility in rats following intravenous (IV) oxymorphone (0.1 mg/kg), atropine (0.1 mg/kg), or saline were monitored to determine whether opioid-induced changes in colonic motility affect antinociceptive measurements when using colorectal distension (CRD) as a nociceptive assay. Polygraph recordings of colonic pressures, contraction frequencies, and the pressure-volume relationship of the stimulus showed that oxymorphone produced a transient increase in contraction frequencies when compared to atropine- and saline-treated rats. The transient increase in contraction frequency caused by oxymorphone declined to baseline levels at 30 min after administration, the time at which the nociceptive threshold for CRD was tested. Neither oxymorphone nor atropine changed baseline pressures or the pressure-volume curve for the balloon stimulus. Antinociceptive results from CRD at 30 min posttreatment showed that only oxymorphone produced significant antinociception. We conclude that oxymorphone does not produce changes in colonic motility that complicate antinociceptive measurements in CRD and that CRD is an effective means of testing opioid-induced visceral antinociception.

Female F0 generation Sprague-Dawley rats received daily oral doses of 0, 0.2, or 2 mg/kg polybrominated biphenyls (PBB) as fireMaster BP-6 from Day 6 of gestation through Day 24 postpartum. Maternal parameters were assessed, and F1 generation offspring were evaluated for growth and survival, as well as physical and behavioral development. No adverse maternal effects were observed nor were there PBB-related effects on survival of the F1 generation or acquisition of developmental landmarks. Crown-rump length of 0.2 and 2 mg/kg male offspring was significantly less than that of controls and 2 mg/kg male and female offspring gained significantly less weight than did controls for the entire 60-day postnatal observation period. An overall evaluation of behavior by multivariate analysis of variance revealed significant PBB-related effects for acquisition of forward locomotion, cliff avoidance, cage emergence, and open-field activity of male and female offspring from dams administered 2 mg/kg. Delays in acquisition of forward locomotion and suppressed open-field activity were the most prominent effects. These indications of growth retardation and neurobehavioral toxicity occurred at concentrations of PBB in offspring body fat in the range of those which have been reported for highly exposed human subjects with neurological sequelae.

Four groups of rats received chlordiazepoxide (CDP): a) intermittently, experiencing hypothermia and rotarod performance (RR) deficit after test doses (contingency); b) chronically, experiencing hypothermia and RR deficit after test doses; c) intermittently, RR preceding test doses and with protection against hypothermia afforded by exposure to heat lamps (nonexperienced, noncontingency); and d) chronically, RR preceding test doses and with protection against hypothermia. After 36 days of chronic CDP (groups 2 and 4) or vehicle (groups 1 and 3), all groups experienced RR and body temperature (BT) drug deficits after test doses of CDP at the postwithdrawal test. Group 1 but not group 3 was tolerant to peak hypothermia of the drug. Both chronic groups (2 and 4) showed marked tolerance to hypothermia. At the postwithdrawal test, after discontinuing chronic CDP or vehicle for 9 days, only groups 2 and 4 lost drug tolerance to hypothermia. After extinction training (daily testing of RR and BT after injecting vehicle over 9 days), group 2 but not group 4 was again less sensitive to CDP-induced hypothermia at the postextinction test. Regarding CDP-induced RR ataxia, group 1 was more tolerant than group 3 at the postchronic test, while group 4 but not group 2 also showed tolerance to ataxia. At the postwithdrawal test, only group 4 lost tolerance to peak RR ataxic effects of CDP. At the postextinction test, only group 1 lost tolerance for ataxia relative to postchronic test results.(ABSTRACT TRUNCATED AT 250 WORDS)

This study was designed to test analgesia, duration, and cardiovascular changes induced by meperidine (MEP) and oxymorphone (OXY) following methoxyflurane (MOF) and halothane (HAL) anesthesia. Eight healthy dogs were given atropine and acepromazine, and anesthesia was induced with thiamylal and maintained with 1.5 minimal alveolar concentration of MOF or HAL for 1 hour during controlled ventilation. Eight treatments were given with each anesthetic: 3 with MEP (0.5, 1.0, and 2.0 mg/kg, IV), 3 with oxymorphone (OXY; 0.05, 0.1, and 0.2 mg/kg, IV), and 2 placebos with sterile water. Test drugs were given at the end of anesthesia when early signs of recovery were evident. Minimal threshold stimulus/response nociception was assessed by use of an inflatable soft plastic colonic balloon. Blood pressures and pulse rate were measured with a noninvasive monitor. Meperidine and OXY were found to be effective analgesics and could be reversed with naloxone. Intravenous administration of 2.0 mg of MEP/kg provided analgesia for 36 +/- 6 minutes and 39 +/- 15 minutes after MOF and HAL, respectively. In contrast, OXY was effective at all 3 doses with effects of IV administration of 0.2 mg of OXY/kg lasting 154 +/- 13 minutes and 152 +/- 12 minutes, after MOF and HAL, respectively. Analgesia could not be demonstrated after anesthesia for acepromazine, MOF, or HAL. Blood pressure was not changed by either anesthetic nor was it influenced by MEP or OXY. Pulse rate was significantly depressed by the higher doses of OXY following HAL, but was not changed by MEP following either anesthetic.(ABSTRACT TRUNCATED AT 250 WORDS)

Butorphanol (0.025, 0.05, 0.1, 0.2, 0.4, and 0.8 mg/kg of body weight, and placebo) was given SC to 8 healthy unmedicated dogs to determine its efficacy for visceral analgesia, using a colonic balloon for minimal threshold nociceptor stimulation. Degree of sedation; systolic, diastolic, and mean arterial pressure; and pulse rate were recorded. The highest 3 dosages, 0.2, 0.4, and 0.8 mg/kg, were found to be most effective, with 0.8 mg/kg the only dosage that was significantly different from control responses at the 45-minute interval. Duration of analgesia ranged from 23 to 53 minutes for all 6 dosages and dosing durations were not significantly different from one another. Blood pressures did not change, but pulse rate was significantly decreased by 0.8 mg of butorphanol/kg. We concluded that butorphanol is an effective visceral analgesic of relatively short duration in the dog.

This study was designed to determine the effective analgesic dose of butorphanol administered intravenously to obtund visceral nociception, as well as to determine duration of this effect. Additionally, cardiovascular changes and sedative effects were defined. Eight healthy dogs were each given five doses of butorphanol (0.025, 0.05, 0.1, 0.2, and 0.4 mg/kg) plus a sterile water placebo intravenously in a randomized blinded format. Antinociception was assessed using an inflatable Silastic balloon inserted into the colon. Blood pressures and pulse rates were measured with a noninvasive monitor. The greatest efficacy and longest duration of antinociception were produced by 0.4 mg/kg of butorphanol, with a duration of 38 +/- 9 min. Arterial blood pressure and pulse rate did not vary at antinociceptive doses. Mild sedation was observed at all doses, which generally lasted longer than the antinociceptive effects. These data suggest that butorphanol can be given alone intravenously to provide visceral antinociception lasting 30-45 min without significant side effects.

Pentobarbital was administered to 4 groups of rats: 1) intermittently before testing on the rotarod (RR) (experienced, EXP), 2) chronically (CHR) before testing on the RR (EXP), 3) intermittently (INT) after being tested on the RR (NONEXP), and 4) chronically (CHR) after being tested on the RR (NONEXP). On postchronic testing, Group 1 (INT/EXP) failed to show tolerance to the RR decrement, related to prechronic scores, while Group 3 (INT/NONEXP) actually showed an enhanced RR decrement. Group 2 (CHR/EXP) and Group 4 (CHR/NONEXP) both exhibited prominent tolerance to RR impairment at the postchronic test, with a nonsignificant trend for greater tolerance in Group 2. The lack of an expressed behavioral tolerance in INT/EXP rats and the enhanced RR decrement in INT/NONEXP subjects at the postchronic test was attributed to repeated use of a towel wrap restraint during the chronic treatment period. When the prechronic tests for INT/EXP animals were separated into the first 3 and last 3 days, pentobarbital impairment of RR during days 4-6 was significantly less than during days 1-3. This tolerance in INT/EXP rats was lost at the postchronic testing, while INT/NONEXP subjects had by then developed an enhanced RR impairment to pentobarbital. Following postchronic testing, chronic pentobarbital (CHR/EXP and CHR/NONEXP groups) and chronic vehicle (INT/EXP and INT/NONEXP groups) were discontinued for 9 days (withdrawal), after which an intermediate dose of the drug was tested on RR performance. Next, 9 days of extinction training involved vehicle injection daily before testing RR performance, after which the intermediate drug dose was again tested. INT/EXP and INT/NONEXP groups showed no change in RR impairment at the postwithdrawal and postextinction tests. However, in CHR/EXP rats pentobarbital tolerance was partly lost at the postwithdrawal test, with a significantly greater loss at the postextinction test.(ABSTRACT TRUNCATED AT 250 WORDS)

The development of behavioral tolerance to pentobarbital-induced hypothermia, as separable from cellular and metabolic tolerance, was established. Pentobarbital (PB) was administered to 4 groups of rats, 2 groups of which received intermittent (INT) IP PB treatment. One of these groups, INT/EXP, experienced the hypothermic (measured as rectal body temperature) drug effect after PB injection. The other group, INT/NONEXP, was monitored for body temperature functions (room temperature) before receiving PB (vehicle administration) and then prevented from experiencing PB-induced hypothermia by maintenance of body temperature with a towel wrap restraint and a heating lamp. The INT/EXP group also received equivalent exposure to this towel wrap after vehicle administration. Two other groups received chronic PB treatment (IP and in ground chow), one with experience for hypothermia after injections (CHR/EXP) and one prevented from experiencing the hypothermia (CHR/NONEXP). These groups also received equivalent exposure to the body temperature (at room temperature) testing and towel wrap restraint, EXP rats after vehicle injections and NONEXP after drug injections. A postchronic test of all groups compared the extent of PB hypothermia to prechronic test effects to assess the degree of tolerance. The INT/EXP group demonstrated behavioral tolerance for PB-induced hypothermia, as contrasted with the INT/NONEXP group which demonstrated little or no tolerance. Prominent tolerance was noted in both chronic groups for PB hypothermia, without a significant difference between them. After the postchronic test, chronic treatment was discontinued for 9 days (withdrawal) followed by 9 days of extinction training (vehicle behavioral testing). The two intermittent groups demonstrated no change in the hypothermic drug response during the postwithdrawal and postextinction drug tests.(ABSTRACT TRUNCATED AT 250 WORDS)

This study was conducted to determine whether blood pressures and pulse rate could be determined accurately by indirect measurements from the front and hind legs of 15- to 40-kg dogs anesthetized with isoflurane. Indirect measurements from each animal were compared to direct measurements obtained from a catheter placed into the abdominal aorta via the femoral artery at four ranges of systolic pressure. When systolic pressure was above 80 mm Hg, indirect measurements were either the same as direct measurements or slightly lower. However, when systolic pressures were below 80 mm Hg, indirect systolic pressure measurements were 6 to 15% higher than direct measurements. Larger differences in diastolic pressures were found, which resulted in differences in mean pressure. The most accurate measurements were found when the cuff width-to-limb circumference ratio was between 0.4 and 0.6 and when systolic pressure was between 80 and 100 mm Hg.

Four groups of rats received ethanol: 1) intermittently while experiencing hypothermia, 2) chronically while experiencing hypothermia, 3) intermittently while protected from hypothermia, and 4) chronically while being protected from hypothermia. On postchronic testing, Group 1 showed tolerance to 2.0 and 2.3 but not 2.7 g/kg ethanol, Group 2 was tolerant to all 3 doses, Group 3 was tolerant to none, and Group 4 was tolerant only to 2.7 g/kg. On withdrawal of chronic ethanol or vehicle, Groups 1 and 2 showed trends to lose tolerance which became significant after subsequent extinction training. The treatments were repeated in other rats up to the postchronic test for tolerance, after which they were killed at 15-120 min after ethanol to assay serum and brain concentrations. Serum and brain levels of ethanol were higher in Groups 2 and 4 despite less intense hypothermia (i.e., no metabolic tolerance). Analysis of covariance indicated less tolerance in Group 1 vs. Group 2 and Group 3 vs. Group 4 for the same brain levels of ethanol (i.e., cellular tolerance in Groups 2 and 4). Therefore, both learned and cellular tolerances were observed in these subjects and appeared to be separable phenomena according to the various treatments imposed.

Doses of d-amphetamine (3.2 mg/kg), fenfluramine (10 mg/kg) and quipazine (8 mg/kg) cause a significant reduction in food intake during a 30-min daily feeding session in food-deprived rats. Pirenperone and ritanserin, 5-HT2 receptor antagonists, significantly blocked the anorectic effect of quipazine, while d-amphetamine and fenfluramine effects were not modified. Metergoline, a non-specific blocker of 5-HT receptors, significantly blocked the anorectic effects of fenfluramine and quipazine, but not the d-amphetamine effect. Pretreatment with alpha- and beta-adrenergic receptor antagonists (prazosin, propranolol and pindolol), dopamine receptor antagonists (haloperidol and pimozide), the catecholamine synthesis inhibitor alpha-methyl-para-tyrosine, and the opioid receptor antagonist naloxone failed to modify the anorectic effects of all three agents, with the exception that quipazine-induced anorexia was significantly reduced by pimozide. These results suggest that the quipazine anorexia is largely mediating through 5-HT2 receptors, although the effect of pimozide remains to be explained. Consistent with previous studies, the fenfluramine effect appears to be mediated through 5-HT1B receptors. Receptors involved in the anorectic effect of higher doses of d-amphetamine are still unidentified by this analysis. Further investigation is required to define the mechanisms by which quipazine and larger doses of d-amphetamine bring about a reduced appetite for food.

Male Sprague-Dawley rats were trained to press a lever on a fixed ratio-40 (FR-40) schedule for food reinforcement. Doses ranging from 0.5 to 16 mg/kg of the mixed narcotic agonist-antagonist cyclazocine (30-min pretreatment) resulted in a dose-dependent decrease in the number of reinforcements obtained and a reciprocal increase in "pausing" (IRT's greater than 10 sec). A 5-min pretreatment with 4 mg/kg of the narcotic antagonist naloxone attenuated the cyclazocine disruption. The 5-HT antagonist metergoline (1 mg/kg; 180-min pretreatment) also blocked cyclazocine effects to approximately the same degree as did naloxone. However, the shift of the dose response pattern of cyclazocine was not parallel for either antagonist. A greater degree of attenuation of the cyclazocine effects was observed when naloxone (4 mg/kg) and metergoline (0.1 mg/kg) were given together, indicating that cyclazocine disruption may be antagonized by either a narcotic antagonist or a 5-HT antagonist, and that these antagonists may operate synergistically. Thus, the behavioral effects of cyclazocine may relate to both opioid and serotonergic components.

Chronotropic and inotropic actions of phencyclidine were studied in spontaneously beating right atrial muscle and electrically paced left atrial muscle preparations isolated from guinea-pig or rat hearts. In right atrial muscle preparations, phencyclidine (10-100 microM) decreased the frequency of spontaneous beating. Guinea-pig and rat heart preparations had similar sensitivities to this action of phencyclidine. The negative chronotropic effect was not altered by atropine. A high concentration of naloxone failed to affect the chronotropic effect of phencyclidine in guinea-pig muscle, but significantly reduced the effect in rat heart muscle preparations. Phencyclidine (1-100 microM) caused positive inotropic effects in both guinea-pig and rat heart left atrial muscle electrically stimulated at 1.5 Hz; rat heart preparations had a higher sensitivity to the positive inotropic action of phencyclidine. The positive inotropic effect was reduced by verapamil, nifedipine and relatively high concentrations of diltiazem, but was not affected by propranolol, phentolamine, tripelennamine, atropine or ryanodine, indicating that the effect is not mediated by adrenergic, histaminergic or cholinergic systems or does not involve ryanodine-sensitive calcium pools. Inactivation of the fast sodium channels by partial membrane depolarization, and subsequent restoration of the contraction by raising the extracellular Ca++ concentration, did not abolish the positive inotropic action of phencyclidine. These results suggest that the negative chronotropic effect of phencyclidine is not mediated by a stimulation of the muscarinic receptor. The positive inotropic effects of phencyclidine seem to result from an increase in Ca++ influx through the slow channels of the cardiac cell membrane.

Gravid rats were treated with methadone, 10 mg/kg/day, or vehicle, from day 5 of gestation to term. The offspring were nursed by foster mothers receiving either methadone or vehicle to form 4 groups: (A) methadone during gestation and lactation, (B) methadone during gestation, (C) methadone during lactation, and (D) no drug treatment. Brain monoamines and metabolites were examined at 21 days of age and found to be decreased in groups A and B. Animals treated comparably to group B and sacrificed at 90 days of age showed no abnormalities in brain monoamines excepting a decrease in dopamine metabolites in limbic areas. Another group treated in utero with methadone was tested at 90 days fo age for shuttle-box avoidance acquisition using massed trials. Methadone-exposed subjects exhibited more avoidances, escapes and intertrial shuttles than controls by the third day of training. These results suggest that subtle but lasting changes in limbic dopamine functions as a consequence of fetal exposure to methadone may make rats hyper-responsive in a massed-trial avoidance procedure in the shuttle-box.

Rats chronically implanted with push-pull cannulas were injected with a pulse of 14C-norepinephrine (NE) into the lateral cerebroventricle under a variety of pretreatment and behavioral conditions. Animals pretreated intraventricularly with 6-hydroxydopamine (Group A) or ascorbic acid vehicle (Group B) were subsequently perpised imder fpur conditions: (1) presentation of a novel, visual stimulus in a one-way avoidance chamber; (2) presentation of the light (CS) followed by shock; (3) training to a high level of avoidance behavior, after which the CS was presented in the absence of opportunity for an avoidance response and in the absence of shock; and (4) after forced extinction, followed by CS without opportunity to aboid and with out presentation of shock. Samples of perfusate from rats subjected to the four test conditions were analyzed by thin-layer chromatography for total 14C in a scintillation counter and for proportion of NE and normetanephrine (NM). During Tests 1 and 4 the 14C perfusion wash-out did not differ from control values for either Group A or B. During Test 2, total radioactivity as well as the proportions of NE and NM increased in the perfusate for both Groups A and B. Presenting the CS without shock (3) resulted in 14C and NE and NM for Group B (vehicle), but not for Group A (6-OHDA). To test for non-specific release unrelated to a brain catecholaminergic function, another group of rats was subjected to identical treatments with the exception that 14C-urea replaced 14C-NE as a pulse-label. In these animals Test 2 (shock) induced an increase in 14C in the perfusate, while Tests 1, 3 and 4 yielded wash-out curves essentially identical to controls.

Lysergic acid diethylamide (LSD) was infused in one microliter volumes into discrete brain regions of rats trained to press a bar for food reinforcement. The sites were chosen as major areas of the brain 5-hydroxytryptamine (5HT) system: the dorsal and median raphe nuclei, dorsal hippocampus, lateral habenular nuclei, and the prefrontal cortex. Following training in a fixed ratio-40 (FR-40) operant behavior rats were implanted for the lateral habenular nuclei, dorsal hippocampus and the prefrontal cortex. Following recovery from surgery, LSD (8.6 to 86 micrograms) or vehicle was infused immediately before a daily operant session. Infusion of vehicle was inactive. LSD produced a dose-dependent decrease in reinforcements and an increase in 10-sec periods of non-responding (pause intervals). LSD was significantly more potent when infused into the dorsal raphe nucleus than following intracerebroventricular (ICV) administration, whereas LSD was less potent when infused into the median raphe, lateral habenula or dorsal hippocampus. ED50s for increases in pause intervals were 9, 13, 23, 25, and 54 micrograms for infusion into the dorsal raphe, prefrontal cortex, dorsal hippocampus, median raphe, and lateral habenular nuclei, respectively. The ED50 for ICV administration in a previous study was 15 micrograms. The ED50 of LSD placed into the prefrontal cortex did not differ significantly from that of the ICV infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

This study reports on tolerance and cross-tolerance to the rotarod (RR)-disrupting effects of various central nervous system (CNS) depressants. Female rats trained on the RR were fed ground chow containing pentobarbital (PB, 2.0 mg/g chow) or methaqualone (MQ, 1.0 mg/g chow) and were injected twice daily (PB) or daily MQ) with 30 mg/kg IP for 6 days. Control rats received ground chow and saline injections. On day 7 the subjects were tested with various doses of PB, MQ, diazepam (DZ), or ethanol (ET) for disruption of RR performance over the time-course of the drug effect (up to 12 hours). Control animals demonstrated a dose-dependent duration of impairment for all 4 agents. Both groups receiving chronic drug showed a prominent decrease in duration of RR impairment after PB, a less marked decrease after MQ, and even less of a decrease after DZ. However, neither chronic drug group showed an appreciable tolerance to the RR disruption of ET, relative to the control group. Based on the time of 50% recovery (RR performance recovering to 90 seconds or more), both chronic treatments resulted in a significant shift of the dose-response curves for PB, MQ and DZ to the right. Therefore, the degree of tolerance and cross-tolerance in rats chronically treated with PB or MQ was dramatic for PB and MQ, was significant for DZ, but was not demonstrable for ET.

Water-deprived female Sprague-Dawley rats were trained in a conditioned suppression of drinking paradigm. Experiment 1 assessed the effects of prior experience with ethanol on the initial treatment deficit of diazepam (1A) and the influence of prior experience with diazepam on the initial treatment effects of ethanol (1B). In Experiment 1A, half the animals received three daily doses of ethanol, while the other half received vehicle for 3 days. All rats then received vehicle followed by 3 days of ethanol treatment. No significant effect of prior experience with ethanol was observed on the diazepam initial treatment deficit. In Experiment 1B, half the animals received vehicle followed by three daily doses of diazepam, while the other half received vehicle. All subjects then received vehicle followed by 3 days of ethanol treatment. No significant effect of prior experience with diazepam was noted on ethanol's initial treatment effects. Experiment 2 assessed the effects of diazepam (0, 1, 2, and 4 mg/kg) and ethanol (0, 0.5, 1 and 2 g/kg) alone and in combination in the conflict test. Diazepam, administered alone, resulted in an antipunishment effect. Ethanol alone did not produce an antipunishment effect. The combination of the two drugs generally decreased both punished and unpunished responding. Further, the CNS depressant effects of these drugs appear to be additive. The qualitative effects of these two drugs are different enough to disallow generalization to each other in a conflict test.

The purpose of the present study was to determine the role of central catecholaminergic neuronal systems in the effects of LSD, DOM and d-amphetamine on fixed ratio (FR) operant responding in rats. Food-deprived male rats were trained to press a bar for food reinforcement on a FR-40 schedule. Control responding on this schedule is characterized by a rapid, constant rate of responding (approximately 100 responses/min) throughout a 40 min test session. LSD and DOM, as with other hallucinogens, produced dose-dependent periods of nonresponding or "pausing," followed by reinstatement of responding at or near the control rate. Administration of the non-hallucinogen, d-amphetamine, did not produce "pausing," but caused the response rate to slow and become erratic. In animals pretreated intraventricularly with 6-hydroxydopamine (6-OHDA; 200 micrograms/10 microliter X 2), the response to LSD and DOM was unchanged, while the response to d-amphetamine was significantly diminished. The neurotoxin significantly decreased brain catecholamines to less than 25 percent of control in al regions examined, without altering 5-HT concentrations in these same regions. These data demonstrate that the effects of LSD and DOM on FR-40 responding are quite different from those of d-amphetamine, and that this difference may be due to the extent of catecholamine involvement in the effects of these agents.

The purpose of the present study was to determine the role of central 5-hydroxytryptamine (5-HT) neuronal systems in the effects of d-lysergic acid diethylamide (LSD), 2,5-methoxy-4-methylamphetamine (DOM), pentobarbital (PB) and methaqualone (MQ) on punished responding in rats. Water-deprived rats were trained to drink from a tube that was electrified at intervals (variable interval 21 sec; 0.03 mA current intensity), electrification being signalled by a tone. In daily 10-min control sessions, these animals accepted a relatively constant number of shocks; water consumption was also quite stable. At maximally effective doses PB, and to a lesser extent MQ, produced large (400-600 percent of control) increases in punished responding with little decrease in water intake. Higher doses of these agents produced a significant depression of unpunished responding (water intake). The hallucinogens, on the other hand, produced only moderate (125-175 percent of control) increases in the number of shock received, yet a similar depression of unpunished responding. Selective destruction of 5-HT neurons by intracerebroventricular administration of the neurotoxin 5,7-dihydroxytryptamine per se produced little change in the number of shocks received or water consumed in controls sessions. This destruction of 5-HT neurons failed to alter the effects of PB or MQ on punished or unpunished responding. The increase in punished responding produced by the hallucinogens, however, was blocked by this destruction of 5-HT neurons. Furthermore, the capacity of the hallucinogens to decrease water intake was significantly potentiated by the neurotoxin pretreatment. These data demonstrate that the effects of the hallucinogens LSD and DOM on conditioned suppression are quite different from those of PB and MQ, and that this difference may be due to the extent of 5-HT involvement in the effects of these agents.

The hypothesis that 5-hydroxytryptamine (5-HT) neurons and/or receptors are involved in the mechanism of action of hallucinogens is supported by the fact that intraventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) selectively destroys central 5-HT neurons in the brain and potentiates the behavioral effects of lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM) and mescaline. The locus in the brain where this potentiation might occur is not known. In the present experiment, the medial forebrain bundle (MFB) was studied because it is the primary tract containing fibers from the cell bodies in the raphe nuclei to forebrain structures receiving 5-HT input. Male rats received 5,7-DHT (6 micrograms/2 microliter) or vehicle injections bilaterally into the MFB; this procedure caused a significant reduction of 5-HT in the cortex, hippocampus and hypothalamus of lesioned rats, but not in the striatum. Regional dopamine and norepinephrine concentrations were not affected by this treatment. The behavioral effects of the hallucinogens were tested in a situation in which the animals pressed a bar under a fixed ratio-40 (FR-40) schedule of food reinforcement. The disruptive effects of LSD on responding were enhanced in the 5,7-DHT-treated animals, while the effects of DOM were diminished; there was no change in the response to mescaline. These data suggest that, while 5-HT neurons are involved in the behavioral effects of hallucinogens, the precise sites and/or mechanisms of action of LSD, DOM and mescaline may differ.

Indole and phenethylamine-type hallucinogenic drugs were studied in an FR-40 operant behavioral procedure programmed to quantify "pausing,"-a behavioral disruption somewhat specific to hallucinatory drug effects. LSD, DOM, DMT and mescaline showed a potency ratio to produce pausing that is well correlated with the hallucinatory potencies of these agents in man. Furthermore, combinations of the hallucinogens interact with potentiation to cause FR-40 pausing, whereas a variety of non-hallucinogenic psychoactive drugs failed to shift the dose-response patterns of pausing for DOM or LSD. Depletion of brain catecholamines by pretreatment with intraventricular 6-OHDA reduced baseline FR-40 rates and attenuated the disruptive effects of d-amphetamine, but failed to modify the dose-response patterns of indole and phenethylamine hallucinogens. On the other hand, pretreatment with intraventricular 5,7-DHT to deplete brain 5-HT potentiated the pause-producing effects of the hallucinogens, although the disruptive effects of phenobarbital were not altered by this pretreatment. Injection of 5,7-DHT into the medial forebrain bundle at the hypothalamic level slightly potentiated LSD, attenuated DOM, and did not affect the pausing produced by mescaline. Metergoline pretreatment shifted the LSD and DMT dose-response curves for pausing to the right by a factor of 2--3, but shifted the DOM and mescaline dose-response patterns to a much greater extent. Metergoline alone slightly increased FR-40 response rates and decreased pausing from baseline levels. The patterns of imparied FR-40 performance induced by d-amphetamine and phenobarbital were unaltered by pretreatment with metergoline. The indole and phenethylamine classes of hallucinogens appear to disrupt this behavior by an agonistic effect at central 5-HT receptors. However, the two classes of drugs may interact with brain 5-HT systems by somewhat different mechanisms.

Food-deprived male rats were trained to press a lever on a fixed ratio-40 (FR-40) operant schedule for food reinforcement. Administration of mescaline (4.0--10.0 mg/kg) immediately before the start of the operant session resulted in a cessation of responding for some portion of the 40-min period ("hallucinatory pause"). The duration of this pause was found to be dose-dependent. Although administration of naloxone alone (1.0-8.0 mg/kg, five minutes prior to the start of the session) had no effect on FR-40 responding per se, pretreatment with this agent significantly potentiated the disruptive effects of mescaline. This potentiation by naloxone was further shown to be dose-dependent. These data suggest that the effects of the phenethylamine hallucinogen mescaline are potentiated by pretreatment with the narcotic antagonist naloxone.

2,5-Dimethoxy-4-methylamphetamine (DOM) was infused into discrete brain regions of rats trained to press a bar for food reinforcement on a fixed ratio-40 (FR-40). Sites were chosen as major areas of the brain 5-hydroxytryptamine (5-HT) system: the dorsal and median raphe nuclei, dorsal hippocampus, lateral habenular nuclei and the prefrontal cortex. Following training in a fixed ratio-40 (FR-40) operant behavior rats were implanted with stainless steel cannulae into the brain area to be examined. Bilateral cannulae were implanted for the lateral habenular nuclei, dorsal hippocampus and the prefrontal cortex. Following recovery from surgery, DOM (20-300 micrograms) was tested on operant behavior by infusing the drug immediately before the operant session. Infusion of vehicle was inactive. DOM produced a dose-dependent decrease in reinforcements and a concomitant increase in 10-sec periods of non-responding (pause intervals). DOM was more potent when infused into the median raphe nucleus than following intracerebroventricular (ICV) administration. DOM was less potent when infused into the dorsal raphe, prefrontal cortex or dorsal hippocampus. Infusion of DOM into the lateral habenular nuclei produced a biphasic dose-response curve. ED50s for increases in pause intervals were 47, 77, 92, 103, and 114 micrograms for infusion into the median raphe, dorsal raphe, prefrontal cortex, lateral habenulae, and dorsal hippocampus, respectively. The ED50 for ICV administration in a previous study was 58 micrograms. The effects of DOM in the lateral habenulae could be divided into two curves; one curve had an ED50 of 69 micrograms, whereas the other had an ED50 of 176 micrograms. Furthermore, the dose-response curve for IP administration of DOM was shifted to the left in animals with cannulae placed into the lateral habenular nuclei. No change was seen in the response to IP administration of DOM in animals cannulated in the remaining sites or in animals with ICV cannulae. Therefore, the effects of DOM in disrupting operant behavior may be more critical with regard to its actions in the lateral habenulae and median raphe. Nonetheless, actions at multiple brain sites probably contribute to the total behavioral effects of the drug.

The present study examined the disruptive effects of the phenethylamine hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM) and the putative 5-hydroxytryptamine (5-HT) agonist quipazine on fixed ratio-40 (FR-40) operant responding alone or after pretreatment with putative 5-HT antagonist metergoline. Food-deprived male rats were trained to bar press on a FR-40 schedule for food reinforcements; control responding under this schedule is characterized by a rapid, constant rate of responding (approximately 100 response/min). In control animals, both DOM and quipazine produced dose-dependent disruptions of FR-40 performance characterized by periods of non-responding or "pausing". Following pretreatment with 1.0 mg/kg, and to a lesser extent 0.1 mg/kg, metergoline (180 min prior to the session) the dose-response curves for the "pausing" produced by both DOM and quipazine were shifted significantly to the right. Moreover, increasing the dose of DOM about 16-fold and that of quipazine about 8-fold appears to completely override the antagonism by 1 mg/kg metergoline. These results suggest that the "pausing" produced by DOM or quipazine is the result of activation of 5-HT receptors.

Indolealkylamine and phenethylamine hallucinogens disrupted responding maintained under a fixed-ratio 40 (FR-40) schedule of reinforcement. LSD, DMT, mescaline and DOM produced dose-dependent decreases in number of reinforcers and increases in 10-sec periods of non-responding (pause-intervals). The 5HT agonist quipazine, as well as the LSD congener lisuride, altered response patterns in a similar manner. The effects of these drugs were examined after pretreatment with pirenperone, an antagonist with specificity toward the 5HT2 receptor with reference to the 5HT1 receptor. The dose-response curves for the phenethylamine hallucinogens were shifted significantly to the right and to a greater degree than were those for the indolealkylamine hallucinogens. Pirenperone also antagonized the effects of quipazine to a degree similar to that observed with the phenethylamine-type hallucinogens. Pirenperone did not significantly shift the dose-response pattern to lisuride. These data suggest that the behavioral disruption induced by these hallucinogens and quipazine relates at least in part to an effect on 5HT2 receptors, while the effects of lisuride do not involve a significant interaction at the 5HT2 receptor.

d-Amphetamine and d-fenfluramine caused different patterns of disruption in a learned maze performance reinforced with food. A 0.8 mg/kg dose of amphetamine increased correct and incorrect (errors) alley entrances as well as earned reinforcers consumed. Larger doses (1.6-3.2 mg/kg) decreased correct responses, increased errors, and resulted in earned reinforcers not being consumed. Metergoline pretreatment did not reverse these deficits. d-Fenfluramine (1.5 and 3.0 mg/kg) reduced correct responses dose- relatedly with a slight increase in errors after the larger dose; all earned reinforcers were consumed. Pretreatment with metergoline reversed the deficit in correct responses but not the errors. Combinations of d-amphetamine and d-fenfluramine produced greater deficits than each drug separately, with fewer correct responses and an increase in reinforcers earned but not consumed. Metergoline pretreatment before the combination did not reverse these effects but increased alley entrances scored as errors. The results indicate that the d-fenfluramine but not the d-amphetamine deficit relates to a 5-hydroxytryptamine (5-HT) mechanism. Furthermore, the enhanced effect of the combination appears to relate to drug interactions not dependent upon a 5-HT component.

The neurochemical effects of DOM and d-amphetamine were compared under several conditions in unanesthetized rats implanted with chronic-indwelling push-pull cannulae in a cerebral lateral ventricle. Brain catecholamine storage sites were previously pulse-labelled with 14-C-norepinephrine administered intraventricularly. During the perfusion of the lateral ventricles with artificial cerebrospinal fluid, the animals were injected i.p. with 1.5 mg/kg of DOM, 2.0 mg/kg of d-amphetamine or 1.0 ml/kg of isotonic saline. Analysis of the perfusate in successive samples indicated an increased efflux of 14-C-radioactivity in rats administered DOM or d-amphetamine. Increased proportions of 14-C-norepinephrine and 14-C-normetanephrine were detected in samples of perfusate 15 to 30 min after drug injection. Pretreatment of other animals with 6-hydroxydopamine intraventricularly, which decreased brain levels of both norepinephrine and dopamine, blocked the increased efflux of 14-C-radioactivity induced by DOM or d-amphetamine. Pretreatment of rats with 6-hydroxydopa i.p., which depleted brain norepinephrine selectively, reduced to about half the d-amphetamine-induced efflux of 14-C-radioactivity for all samples during the time course of the effect. However, animals pretreated with 6-hydroxydopa and then tested for DOM effects showed a different pattern of 14-C-radioactivity efflux. The efflux for the initial samples was increased as with the DOM control, but the 6-hydroxydopa pretreatment attuated the DOM-induced efflux for the later samples. The results suggest DOM and d-amphetamine share qualitatively similar effects in releasing and/or blocking the reuptake of catecholamines at brain periventricular nerve terminals. Nevertheless, DOM appears to differ from d-amphetamine in the temporal pattern of net catecholamine release.

Effects of chronic treatment with the monoamine oxidase inhibitors phenelzine and isocarboxazid on disruption of FR-40 operant responses by 5-HT agonists have been studied. Three groups of rats that were trained in the FR-40 operant schedule showed marked disruption by 0.1 mg/kg IP lysergic acid diethylamide (LSD), 2 mg/kg IP quipazine (Q), 0.05 mg/kg SC 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT), and 1 mg/kg SC (m-trifluoromethyl-phenyl)piperazine (TFMPP), administered twice weekly in random order. Subsequently, one group received daily IP injection of phenelzine (5 and 10 mg/kg), the second group received 5 mg/kg IP of isocarboxazid, and the third group received vehicle (0.5% methyl cellulose) for 24 days (Period 1 and Period 2). For these periods and 12 days after discontinuing the MAOI treatments (Washout Period), test doses of 5-HT agonists were evaluated for their effects to decrease reinforcements (R) and increase pauses (P). No change in sensitivity to the LSD, Q and TFMPP effects on FR-40 behavior was observed in the vehicle-treated group. However, an attenuated effect of 8-OHDPAT was found in this group. In phenelzine- and isocarboxazid-treated rats the disruption of FR-40 responses by LSD and 8-OHDPAT were significantly reduced during Period 1, Period 2 and Washout Period. A significantly less effect on disruption in FR-40 responses by quipazine and TFMPP during Period 2 and the Washout Period was also seen. Since MAO inhibitors appear to down-regulate both 5-HT1 and 5-HT2 binding sites in brain, the attenuated effects of the 5-HT agonists were anticipated.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects on a fixed ratio-40 (FR-40) operant behavior of intracerebroventricular (ICV) administration of the hallucinogens lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM), mescaline or the non-hallucinogenic LSD-analogue lisuride were compared with intraperitoneal (IP) administration. Infusion of LSD (8.5 to 34 micrograms) into the left lateral ventricle produced a dose-dependent decrease in reinforcers and an increase in 10-sec periods of non-responding (pause intervals). The time-course of LSD showed a shorter latency to onset after ICV than IP administration. The ED50 for doses increasing pause intervals by ICV administration was 15 micrograms. This disruption was greater than that produced by IP administration of equivalent doses of LSD (IP ED50: 19 micrograms). DOM (40 to 120 micrograms) infused into the lateral ventricle also produced a dose-dependent disruption of FR-40 behavior. ICV DOM also showed a rapid onset to peak effects, but a slower offset than LSD, and was 3 times more potent than systemic administration (ED50s: 58 micrograms ICV vs. 153 micrograms IP). Mescaline was much more potent in disrupting FR-40 behavior by the ICV route than by IP administration. The ICV ED50 for doses of mescaline increasing pause intervals was 74 micrograms, in contrast to an ED50 following systemic administration of 2251 micrograms, demonstrating a 30-fold difference in potency. Lisuride administered via the ICV route was no more potent than by IP administration with ED50s of 4 micrograms ICV and 4 micrograms IP. Lower doses of lisuride administered by both routes had a similar effect over time on pause intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Three groups (n = 6) of male Sprague-Dawley rats were trained to barpress for food reinforcement on a fixed ratio-40 schedule. Each group then received one of three doses of haloperidol (0.125, 0.25, or 0.5 mg/kg, i.p.) according to the following treatment regimen: Baseline, Presession, Postsession, Presession, Postsession, Baseline, Extinction. Each treatment lasted six days each. Only the Presession and Extinction conditions resulted in a significant decrease in the number of reinforcements earned. The number of inter-response times greater than ten sec was inversely related to the number of reinforcements earned. The fact that chronic presession, but not postsession treatment, significantly decreased the number of reinforcements earned would favor an anhedonia interpretation over one postulating cumulative motor deficits. In any event, prior concurrent experience with the drug effect and the operant behavior appears to be critical to the decrement induced by haloperidol.

Doses of LSD, quipazine, 8-OHDPAT and TFMPP were established that prominently disrupted FR-40 operant response pattern in two groups of rats. Subsequently, one group received daily intraperitoneal (IP) injections of imipramine, 2.5 mg/kg, for 4 weeks, then 10 mg/kg for 2 additional weeks. The second group received 5 mg/kg/day, IP, of trazodone for the first 4 weeks, then 20 mg/kg/day for the next two weeks. For these periods and the 3 weeks after discontinuing the chronic drug treatments (washout), test doses of the 4 agonists were evaluated twice weekly in random order for their effects to decrease FR-40 reinforcements and increase pauses. No consistent, systematic changes in sensitivity to the agonist effects on FR-40 behavior were observed during chronic drug treatments, although significant effects were at times observed. However, during the washout period in the imipramine group, both LSD and 8-OHDPAT effects on reinforcements were reversed to baseline levels. The effect of 5-OHDPAT on pauses during washout in this group was also attenuated. During washout in the trazodone group, the 8-OHDPAT-induced pausing and loss of reinforcements was reduced so as to be not significantly different from baseline values. Previous studies have demonstrated antagonism of LSD- and quipazine-induced disruption of FR-40 by pretreating with the 5-HT2-selective antagonist pirenperone (28). Since chronic antidepressants down-regulate brain 5-HT2 binding sites, the effects of LSD and quipazine were expected to be attenuated, which was not the case.(ABSTRACT TRUNCATED AT 250 WORDS)

A novel form of experimentally-induced conflict behavior based on the conditioned suppression of drinking (CSD) is described and compared with two conventional animal models of human anxiety--a modified Geller-Seifter and an Estes-Skinner (Conditioned Emotional Response) procedure. The CSD procedure offered significant advantages over the two operant procedures in that the session duration was short (10 min) and the acquisition of stable behavioral baselines was rapid (approximately 2 weeks). Like the more conventional procedures, the CSD paradigm permitted the simultaneous determination of drug effects on shock-suppressed and nonsuppressed responding as estimates of antianxiety and sedative properties, respectively. With the CSD procedure, the anticonflict profiles for the benzodiazepines were highly correlated with their relative clinical antianxiety potency. Therefore, the CSD procedure appears to be a valuable tool in screening for possible antianxiety agents as well as in the behavioral testing of mechanism of action hypotheses regarding such agents.

Seven food deprived male rats were trained to press a bar on a fixed ratio-40 (FR-40) schedule of food reinforcement. Administration of 0.5 mg/kg 2,5-dimethoxy-4-methyl amphetamine (DOM) immediately before the start of the session resulted in cessation of responding for some portion of the 40-min test session. Three successive days of p-chlorophenylalanine (PCPA) administration (100 mg/kg) 30 min after each session reduced 5-hydroxytryptamine (5-HT) to 15-26% of control concentrations in various brain regions but did not alter control rates of responding under the FR-40 schedule. Administration of 0.5 mg/kg DOM following this PCPA pretreatment resulted in a greater amount of nonresponding than observed earlier. These data suggest that the effects of the phenethylamine hallucinogen DOM are enhanced by disruption of 5-HT neuronal activity.

Administration of the indolealkylamine hallucinogen d-lysergic acid diethylamide (LSD), the phenethylamine hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM) and the putative 5-hydroxytryptamine (5-HT) agonist quipazine all produced a dose-dependent decrease in fixed ratio (FR-40) response rates and a concomitant increase in the number of 10-second pause intervals. Although naloxone (4.0 mg/kg) had no effect on FR-40 responding per se, the pause-producing effects of LSD and, to a lesser extent, DOM were potentiated by pretreatment with naloxone. The action of quipazine on reinforcers was unaffected by combination with naloxone, while the effect on pause intervals was slightly attenuated by naloxone pretreatment. These data and previous studies suggest that the pause-producing effects of indolealkylamine and phenethylamine hallucinogens reflect their activation of a selective portion of brain 5-HT receptors. The potentiation of these effects by naloxone may relate to a modulation of central 5-HT systems by endogenous opioid mechanisms tending to restore an imbalance in various 5-HT pathways caused by the hallucinogenic 5-HT agonists. The more generalized disruptive effects of quipazine on brain 5-HT systems may be less susceptible to the endogenous opioid modulation or may actually combine with it to induce a greater disruption.

The present study was designed to examine the role of 5-hydroxytryptamine (5-HT) neurons in the behavioral effects of d-lysergic acid diethylamide (LSD), an indolealkylamine hallucinogen, 2.5-dimethoxy-4-methylamphetamine (DOM) and mescaline, phenethylamine hallucinogens, and phenobarbital, a non-hallucinogen. Male rats, maintained at 70-80% of their free-feeding weights, were trained to press a lever for food pellet reinforcement on a fixed ratio-40 operant schedule. When trained, these rats responded at a constant, rapid rate (approximately 100 responses/min) during daily 40 min test sessions. Administration of hallucinogens caused an abrupt cessation of responding (a "pause"), for some portion of the session. The duration of this pause was dose-dependent for LSD (12.5-100 micrograms/kg), DOM (0.125-1.0 mg/kg) and mescaline (7.1-14.2 mg/kg). On the other hand, phenobarbital (12.5-50 mg/kg) did not cause pausing, but resulted in slowed, erratic intrasession response rates. When the same tests were repeated in rats that had previously received an intracerebroventricular injection of 5,7-dihydroxyptamine (5,7-DHT) the dose-response curves for the pausing induced by all three hallucinogens were shifted to the left, while the behavioral disruption produced by phenobarbital was unaltered. In these animals the 5-HT but not the norepinephrine concentrations was markedly reduced in all brain regions examined. These results suggest that 5-HT neurons are involved with the behavioral effects of hallucinogens but not of phenobarbital.